CN103992391B - A kind of method purifying terlipressin - Google Patents
A kind of method purifying terlipressin Download PDFInfo
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- CN103992391B CN103992391B CN201410051178.9A CN201410051178A CN103992391B CN 103992391 B CN103992391 B CN 103992391B CN 201410051178 A CN201410051178 A CN 201410051178A CN 103992391 B CN103992391 B CN 103992391B
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Abstract
The present invention relates to a kind of method purifying terlipressin, its feature comprises the following steps: step 1, dissolves terlipressin crude product water, regulates pH to 34；Step 2, uses the ion-pair A containing surfactant to rinse C18 reverse phase filler post；Step 3, is loaded into step 1 solution in C18 reverse phase filler；Step 4, Gradient program is: the original state Mobile phase B of gradient is 5%, keeps 5 min, then Mobile phase B ratio increases in 60 min 30%, collects part purpose peak eluting fraction；Step 5, after NF membrane desalination, obtains sterling terlipressin through freeze-drying.
Description
Technical field
The present invention relates to the purification process of a kind of polypeptide drug terlipressin, be that one has long-acting blood vessel and adds
The purification process of pressure element analog.
Background technology
Terlipressin, illustrious name is: Terlipressin, and for a kind of ring type polypeptide, structural formula is as follows:
Chemical formula is as follows:
。
Terlipressin is the triglycine-lysine-pitressin of Prof. Du Yucang, is that the vasopressing of synthesis is similar to
Thing, it is a kind of pro-drug, and itself is inactive, and in vivo through aminopeptidase effect, 3 glycyl sloughing its N-terminal are residual
After base, slow " release " goes out activated lypressin, and therefore terlipressin is equivalent to one and can release with steady rate
Release the bunker of lypressin.The Main Function of terlipressin is to shrink visceral vessel smooth muscle, reduces internal organ blood
Flow (as reduced the blood flow in mesenterium, spleen, uterus etc.), thus reduce portal venous flow, reduce portal venous pressure, also can make simultaneously
It for the smooth muscle such as esophagus and uterus, is a kind of medicine safely and effectively treating Acute Venous varicose bleeding.
Chinese patent CN201110171151.X discloses the preparation method of a kind of terlipressin, concretely comprises the following steps: first
To terlipressin, thick peptide solution carries out reverse-phase chromatography gradient elution purifying, then uses anion exchange method by trifluoroacetate
Change into acetate.This method total recovery 43%, purity is 99.60 %, and can not efficiently separate terlipressin and impurity [β Asp8]-
Terlipressin.
In the building-up process of existing terlipressin, Asn hydrolysis can produce impurity [Asp8]-terlipressin, and
[Asp8]-terlipressin can be by forming intermediate state and then generation impurity [the β Asp of succinimide8]-terlipressin,
[βAsp8]-terlipressin is from the impurity that main peak is nearest, maximum in terlipressin known impurities, and its structure is as follows:
。
This impurity is one of maximum impurity of toxicity, and extremely unstable, and the existence of this impurity has a strong impact on Te Lijia
The content of pressure element and use safety.It is thus desirable to find effective method to remove it and reach gold standard rank
0.1 below %.The present inventor studies discovery, and the means of this impurity prior art are difficult to remove, though some methods can be removed
Part, but removal effect is undesirable, it is difficult to reach gold standard rank and easily cause the reduction of terlipressin yield own simultaneously.
To this end, how the present inventor's primary study removes the removal of impurity [β Asp8] terlipressin and the yield that do not affects terlipressin ask
Topic.
The present inventor uses existing purification process, purifies the terlipressin prepared by solid-phase synthesis, sends out
Existing impurity [β Asp8The content of]-terlipressin is all unable to reach pre-0.1 % that fixes one's aim.To this end, the present inventor is to special profit pressurization
The purification process of element is studied, thus has obtained technical scheme.
Content of the invention
It is an object of the invention to provide the purification process of the terlipressin of a kind of high yield, high-purity and low cost.
The technical issues that need to address of the present invention are: select the purification process of a kind of terlipressin, solve (1) terlipressin finished product
Purity is not high, and (2) terlipressin product yield is not high, (3) terlipressin and impurity [β Asp8]-terlipressin is not
The problem that can efficiently separate.
In the present invention, some conventional abbreviations and term have following meanings；
Fmoc: fluorenylmethyloxycarbonyl
The amino acid of Fmoc-AA: fluorenylmethyloxycarbonyl protection
TBu: the tert-butyl group
HoBt: 1-hydroxy benzenes a pair of horses going side by side triazole
DIC: N, N '-Diisopropylcarbodiimide
Gly: glycine
Lys: lysine
Pro: proline
Asn: asparagine
Gln: glutamine
Phe: phenylalanine
Tyr: tyrosine
Cys: cysteine
Trt: trityl
Boc: tertbutyloxycarbonyl
DMF: N, N '-dimethylformamide
Piperidine: hexahydropyridine
TFA: trifluoracetic acid
MeOH: methyl alcohol
DCM: dichloromethane.
The technical scheme is that
Use the RP chromatography containing surfactant can make terlipressin and impurity [β Asp8]-terlipressin
Efficiently separated.
There is provided the purification process of a kind of terlipressin for this present invention, it is characterised in that step is as follows:
Terlipressin crude product water is dissolved, regulates pH to 3-4 by step 1；
Step 2, uses the ion-pair A containing surfactant to rinse C18 reverse phase filler post；
Step 3, is loaded into step 1 solution in C18 reverse phase filler；
Step 4, Gradient program is: the original state Mobile phase B of gradient is 5 %, keeps 5 min, then 60 min
Interior 30 % that increase to Mobile phase B ratio, collect part purpose peak eluting fraction；
Step 5, after NF membrane desalination, obtains sterling terlipressin through freeze-drying.
Wherein, C18 reverse phase filler post is (10 μm, 50 mm × 250 mm)；
Mobile phase A: 5 mmol/L ammonium dihydrogen phosphate+25 mmol/L surfactants (use phosphoric acid to adjust pH:3-4)；
Mobile phase B: acetonitrile；
Gradient program is: original state Mobile phase B is 5 %, keeps 5 min, then by Mobile phase B ratio in 60 min
Increase to 30 %, collect part purpose peak eluting fraction；Flow velocity is: 80 mL/min；Detection wavelength is 220 nm.
Preferred operating procedure is as follows:
Step 1, sample treatment:
It is dissolved in the 1.00 thick peptides of g terlipressin in 100 mL pure water, use phosphorus acid for adjusting pH to be 3.5 ± 0.2；
Step 2, balance:
The mobile phase A using 95 % rinses C18 reverse phase filler post 5 min；Wherein, C18 reverse phase filler post for (10 μm, 50
mm ×250 mm)；Mobile phase A: 5 mmol/L ammonium dihydrogen phosphate+25 mmol/L decane sulfonate (use phosphoric acid tune pH:
3.5)；Mobile phase B: acetonitrile；
Step 3, loading:
Prepare sample solution loading in post；
Step 4, wash-out:
Gradient program is: original state Mobile phase B is 5 %, keeps 5 min, then in 60 min increases Mobile phase B ratio
To 30 %；Flow velocity is: 80 mL/min；Detection wavelength is 220 nm；Collect the eluting fraction more than 99.80 % for the purpose peak purity,
Middle control detection: by C18 (5 um, 150 × 3.0mm) chromatographic column；(take ammonium sulfate 1.32 g with ammonium sulphate buffer, add water 2000
ML, adds sulfuric acid 0.4 mL)-methyl alcohol (1440:320) is mobile phase A, ammonium sulphate buffer-methyl alcohol (550:240) is flowing phase
B；Flow velocity is 0.6m1/min；Column temperature is 30 DEG C；Detection wavelength is 210 nm；The original state of gradient is 15 % flowings
Phase B, keeps 35 min, then Mobile phase B rises in 20 min 100 %, keeps 5 min, then return in 1 min
Original state, keeps 19 min；
Step 5, desalination:
By eluting fraction through NF membrane desalination, collect trapped fluid；
Step 6, lyophilized:
Trapped fluid is obtained sterling terlipressin through lyophilized.
Further illustrate beneficial effects of the present invention below by way of experimental data:
The method using Chinese patent CN201310214366.4 purifies crude product terlipressin, measures impurity [β Asp8]-
The content of terlipressin is as follows: 0.21 %；
The method using Chinese patent CN201210248083.7 purifies crude product terlipressin, measures impurity [β Asp8]-
The content of terlipressin is as follows: 0.33 %；
The method using Chinese patent CN201210214758.6 purifies crude product terlipressin, measures impurity [β Asp8]-
The content of terlipressin is as follows: 0.40 %；
The method using Chinese patent CN201110171151.X purifies crude product terlipressin, measures impurity [β Asp8]-
The content of terlipressin is as follows: 0.47 %；
The method using the present invention purifies crude product terlipressin, measures the content of impurity [β Asp8]-terlipressin such as
Under: 0.03 %.
The method of the present invention obtains through screening, and screening process is as follows:
1st, the selection of surfactant:
Sodium hexanesulfonate；Sodium heptanesulfonate；Decane sulfonate；Dodecyl sodium sulfate
2nd, the selection of gradient elution program:
1.:；2.:
3rd, the selection of buffer salt:
Ammonium sulfate；Ammonium dihydrogen phosphate.
Propose 16 kinds of experiment conditions for this:
Experiment condition 1:(1) sample treatment: the 10.00 g terlipressin dissolving crude products obtaining synthesis in solid state are in 1000
In mL pure water, phosphorus acid for adjusting pH is used to be 3.5 ± 0.2；
(2) balance: use the mobile phase A flushing of 95 % to prepare post 5 min, wherein, C18 reverse phase filler post for (10 μm,
50 mm ×250 mm)；Mobile phase A: 5 mmol/L ammonium dihydrogen phosphate+25 mmol/L sodium hexanesulfonates (use phosphoric acid tune pH:
3.5)；Mobile phase B: acetonitrile；
(3) loading: prepare sample solution loading in post；
(4) elute: Gradient program is: the original state Mobile phase B of gradient is 5 %, keeps 5 min, then in 60 min
Mobile phase B ratio is increased to 30 %；Flow velocity is: 80 mL/min；Detection wavelength is 220 nm；Collect purpose peak purity to be more than
The eluting fraction of 99.80 %, middle control detects: by C18 (5 um, 150 × 3.0mm) chromatographic column；(take sulphur with ammonium sulphate buffer
Acid ammonium 1.32 g, add water 2000 mL, adds sulfuric acid 0.4 mL)-methyl alcohol (1440:320) is mobile phase A, ammonium sulphate buffer-
Methyl alcohol (550:240) is Mobile phase B；Flow velocity is 0.6m1/min；Column temperature is 30 DEG C；Detection wavelength is 210 nm；Gradient
Original state be 15 % Mobile phase B, keep 35 min, then Mobile phase B risen to 100 % in 20 min, keep 5
Min, then returns to original state in 1 min, keeps 19 min；
(5) desalination: the experiment condition of desalination: nanofiltration membrane component is: rolling；The material of nanofiltration membrane component is: acetate fiber
Element；Temperature in nanofiltration operation is: 20-50 DEG C；Pressure is: 0.4 Mpa-1.0 Mpa；DK1812C-34D nanofiltration membrane component
Molecular cut off is 300 Da；WTM-1812G laboratory NF membrane separation equipment is used to receive above-mentioned eluting fraction solution
Filter desalination, circulates 8 hours, obtains solution 800 mL after desalination, obtains terlipressin fine peptide after being lyophilized.
Experiment condition 2-16, experimental implementation is as shown in experiment condition 1, and each experiment condition and experimental result are as follows:
Result above shows, the purification effect of experiment condition 7 is optimum.
The invention has the beneficial effects as follows: the terlipressin providing a kind of high-purity, high yield and low cost purifies
Method.
Brief description
Fig. 1 terlipressin thick peptide HPLC spectrogram
The thick peptide of Fig. 2 terlipressin prepares spectrogram
Fig. 3 terlipressin fine peptide HPLC spectrogram
Fig. 4 terlipressin reference substance HPLC spectrogram
Fig. 5 terlipressin fine peptide mass spectrogram.
Detailed description of the invention
Embodiment 1:
The synthesis in solid state of terlipressin: scale is the terlipressin synthesis of 10 mmol
(1) peptide resin deprotection: the Rink amide AM resin (substitution value is 0.72 mmol/g) of 13.89 g is added
Enter in solid phase reaction post, with DMF wash 1 time, after DCM swellable resins 30 min, use volume ratio be 1:4 piperidines and
Deprotection liquid reaction 5 min of DMF composition, DMF washs 1 time, the deprotection of the piperidines using volume ratio to be 1:4 and DMF composition
Liquid reacts 10 min, and DMF washs 6 times.
(2) coupling: by 8.92 g Fmoc-Gly-OH(30 mmol) and 4.05 g HOBt(30 mmol) use solvent DMF
Dissolving, ice bath chilling temperature is 0-10 DEG C, adds 5 mL DIC(30 mmol), join in reaction column after activating 5min and take off
The resin of complete protection reacts, and after reacting 2 hours, judges reaction end, if tree with ninhydrin method detection at 25-35 DEG C
Fat water white transparency, then it represents that reaction is completely；Resin develops the color, then it represents that reaction not exclusively, needs to react 1 hour again, and this judges mark
Standard judges reaction end with ninhydrin method detection be applicable to subsequent amino-acid coupling.
(3) deprotect: the piperidines using volume ratio to be 1:4 and deprotection liquid reaction 5 min of DMF composition, DMF washing 1
Secondary, the piperidines using volume ratio to be 1:4 and deprotection liquid reaction 10 min of DMF composition, DMF washs 6 times, removes Fmoc protection
Base.
(4) coupling: repeat the step that above-mentioned removing Fmoc protects and adds corresponding amino acid couplings, according to terlipressin
Main chain peptide sequence, is sequentially completed: Fmoc-Lys (Boc)-OH, Fmoc-Pro-OH, Fmoc-Cys (Trt)-OH, Fmoc-Asn
(Trt)-OH、Fmoc-Gln(Trt)-OH 、Fmoc-Phe-OH 、Fmoc-Tyr(tBu)-OH 、Fmoc-Cys(Trt)-OH 、
Fmoc-Gly-OH、Fmoc-Gly-OH、Fmoc-Gly-OH。
(5) aoxidizing: dissolve the DCM that 7.62g iodine (30 mmol) adds 200 mL, add in above-mentioned peptide resin, stirring is anti-
Pumping after answering 4 hours, DMF washs 6 times.
(6) deprotect: the piperidines using volume ratio to be 1:4 and deprotection liquid reaction 5 min of DMF composition, DMF washing 1
Secondary, the piperidines using volume ratio to be 1:4 and deprotection liquid reaction 10 min of DMF composition, DMF washs 6 times.
(7) receiving sample: coupling finishes, washing 3 times with DMF, DCM washs 3 times, and MeOH washs 3 times, and DCM washs 3 times, MeOH
Wash 3 times, drain and obtain 32.60 g terlipressin-Rink amide AM resins.
(8) crack: above-mentioned 32.60 g terlipressin-Rink amide AM resins are joined three mouthfuls of circles of 500 mL
In end flask, by TFA: thioanisole: volume ratio configuration lysate 330 mL of methyl phenyl ethers anisole=90:5:5, lysate is added
State in resin, room temperature reaction 2 hours, filters, the resin after cracking with a small amount of TFA washing 3 times, merging filtrate, concentrates, will concentrate
After liquid join in ice ether and precipitate 1 hour, centrifugal, absolute ether centrifuge washing 6 times, vacuum drying, obtain Te Lijia
Pressure element thick peptide 12.30 g, HPLC purity 88.20 %(Fig. 1), synthesis yield 85 %.
The terlipressin crude product that said method obtains is purified using the following method:
(1) sample treatment:
The 12.30 g terlipressin dissolving crude products obtaining synthesis in solid state, in 1230 mL pure water, use phosphoric acid to adjust
Joint pH is 3.5 ± 0.2.
(2) balance
Post 5 min is prepared in the mobile phase A flushing using 95 %；Wherein, C18 reverse phase filler post for (10 μm, 50 mm ×
250 mm)；Mobile phase A: 5 mmol/L ammonium dihydrogen phosphate+25 mmol/L decane sulfonate (use phosphoric acid to adjust pH:3.5)；Stream
Dynamic phase B: acetonitrile.
(3) loading
Prepare sample solution loading in post.
(4) elute
Gradient program is: the original state Mobile phase B of gradient is 5 %, keeps 5 min, then by Mobile phase B in 60 min
Ratio increases to 30 %；Flow velocity is: 80 mL/min；Detection wavelength is 220 nm；Collect purpose peak purity washing more than 99.80 %
De-cut, middle control detects: by C18 (5 um, 150 × 3.0mm) chromatographic column；With ammonium sulphate buffer (take ammonium sulfate 1.32 g,
Add water 2000 mL, adds sulfuric acid 0.4 mL)-methyl alcohol (1440:320) is mobile phase A, ammonium sulphate buffer-methyl alcohol (550:
240) it is Mobile phase B；Flow velocity is 0.6m1/min；Column temperature is 30 DEG C；Detection wavelength is 210 nm；The original state of gradient
It is 15 % Mobile phase B, keep 35 min, then Mobile phase B is risen to 100 % in 20 min, keep 5 min, then 1
Return to original state in min, keep 19 min.
(5) desalination
The experiment condition of desalination: nanofiltration membrane component is: rolling；The material of nanofiltration membrane component is: cellulose acetate；Nanofiltration is grasped
Temperature in work is: 20-50 DEG C；Pressure is: 0.4 Mpa-1.0 Mpa；
The molecular cut off of DK1812C-34D nanofiltration membrane component is 300 Da；WTM-1812G laboratory NF membrane is used to divide
From equipment, nanofiltration desalination is carried out to above-mentioned eluting fraction solution, circulate 8 hours, obtain solution 1000 mL after desalination, after being lyophilized
To 6.26 g, purity: 99.82 %(Fig. 3), total recovery: 51 %.
(6) impurity [β Asp8The assay of]-terlipressin
Take above-mentioned terlipressin fine peptide, use high performance liquid chromatography checked for impurities [β Asp8Containing of]-terlipressin
Amount.
Impurity [β Asp8The cubage formula of]-terlipressin is as follows:
[βAsp8The content of]-terlipressin=terlipressin reference substance content × [β Asp8Face ,]-terlipressin peak
Long-pending × correction factor/%=92.25 % × 0.416, terlipressin reference substance peak area × 100 × 1.00/1489.574 × 100
%=0.03 %。
Note: terlipressin reference substance is consistent with sample size with the testing conditions of terlipressin fine peptide, is all: 25 μ l.
Correction factor [β Asp8Correction factor=1.00 of]-terlipressin；
Terlipressin reference substance concentration: 1.0 mg/mL；
Terlipressin reference substance peak area: 1489.574 mAU*min (Fig. 4)；
Terlipressin reference substance content: 92.25 %；
Terlipressin fine peptide configuration concentration: 1.0 mg/mL；
[βAsp8]-terlipressin peak area: 0.416 mAU*min.
Claims (2)
1. purifying a method for terlipressin, the method uses C18 reverse phase filler, and flowing uses mutually and contains surfactant
Ion-pairing agent, the impurity in finished product terlipressin [β Asp8]-terlipressin content can be made to be reduced to less than 0.1%,
It is characterized in that, said method comprising the steps of:
Terlipressin crude product water is dissolved, regulates pH to 3-4 by step 1；
Step 2, uses the ion-pair A containing surfactant to rinse C18 reverse phase filler post；
Step 3, the solution obtaining step 1 is loaded in C18 reverse phase filler post；
Step 4, Gradient program is: the original state Mobile phase B of gradient is 5%, keeps 5min, then will stream in 60min
Dynamic phase B ratio increases to 30%, collects part purpose peak eluting fraction；Flow velocity is 80mL/min；Detection wavelength is 220nm；
Step 5, after NF membrane desalination, obtains sterling terlipressin through freeze-drying；
Wherein, C18 reverse phase filler post is 10 μm, 50mm × 250mm；
Described surfactant is: in sodium hexanesulfonate, sodium heptanesulfonate, decane sulfonate, dodecyl sodium sulfate
Kind, mobile phase A: 5mmol/L ammonium dihydrogen phosphate+25mmol/L surfactant, use phosphoric acid to adjust pH:3-4；
Mobile phase B: acetonitrile.
2. method according to claim 1, is characterized in that: comprise the following steps:
Step 1, sample treatment:
It is dissolved in thick for 1.00g terlipressin peptide in 50-100mL pure water, use phosphorus acid for adjusting pH to be 3.5 ± 0.2；
Step 2, balance
The ion-pair A containing surfactant is used to rinse C18 reverse phase filler post 5min；
Step 3, loading
It is loaded into sample solution in C18 reverse phase filler post；
Step 4, wash-out
Gradient program is: the original state Mobile phase B of gradient is 5%, keeps 5min, then in 60min increases Mobile phase B ratio
To 30%；Flow velocity is 80mL/min；Detection wavelength is 220nm；Collect the eluting fraction more than 99.80% for the purpose peak purity；
Step 5, desalination
By eluting fraction through NF membrane desalination, collect trapped fluid；
Step 6, lyophilized
Trapped fluid is obtained sterling terlipressin through lyophilized.
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| CN104761618A (en) * | 2015-01-06 | 2015-07-08 | 苏州天马医药集团天吉生物制药有限公司 | Terlipressin purification preparation method |
| CN105131079B (en) * | 2015-07-25 | 2018-09-14 | 济南康和医药科技有限公司 | A kind of purification process of desmopressin acetate |
| CN105153284B (en) * | 2015-08-18 | 2022-05-31 | 浙江和泽医药科技股份有限公司 | Method for purifying linaclotide |
| CN105017401B (en) * | 2015-08-18 | 2022-05-31 | 浙江和泽医药科技股份有限公司 | Purification method of ziconotide |
| CN105301156B (en) * | 2015-10-12 | 2017-05-24 | 天津红日药业股份有限公司 | Related substance analysis method for terlipressin for injection |
| CN110658297B (en) * | 2019-10-30 | 2021-12-10 | 海南通用三洋药业有限公司 | Method for detecting high-molecular polymer in terlipressin for injection |
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| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
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| CB02 | Change of applicant information |
Address after: 310018 Hangzhou economic and Technological Development Zone, Zhejiang, No. 6 Avenue, No. 452 Applicant after: ADLAI NORTYE BIOPHARMA Co.,Ltd. Address before: 310018 Hangzhou economic and Technological Development Zone, Zhejiang, No. 6 Avenue, No. 452 Applicant before: HANGZHOU ADLAI NORTYE PHARMACEUTICAL TECHNOLOGY Co.,Ltd. Address after: 310018 Hangzhou economic and Technological Development Zone, Zhejiang, No. 6 Avenue, No. 452 Applicant after: HANGZHOU ADLAI NORTYE PHARMACEUTICAL TECHNOLOGY Co.,Ltd. Address before: 310018 Hangzhou economic and Technological Development Zone, Zhejiang, No. 6 Avenue, No. 452 Applicant before: Hangzhou Sinopep Pharmaceutical Inc. |
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| COR | Change of bibliographic data | ||
| C14 | Grant of patent or utility model | ||
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